Methods and Devices for Delivering Drugs Using Drug-Delivery or Drug-Coated Guidewires

ABSTRACT

The present invention relates to a method of delivering drugs having e.g., anti-proliferative activity in the vascular, preferably, the cardiovascular, system locally or systematically using an at least partially drug-coated guidewire. The drug-coated guidewire, particularly an expansion member or portion thereof, is brought into contact with the target tissue or in circulation and the drugs are quickly released into the area surrounding the device in a short time after the contact step. Once the therapeutic drugs are released, they are quickly and effectively absorbed by the surrounding cells or circulation.

FIELD OF THE INVENTION

The present invention relates to the field of medicinal devices andtheir use in delivering drugs or agents (including biological substancessuch as cells) to a particular tissue or body lumen for local orsystemic effect. In general, the present invention relates topercutaneous transluminal devices and to methods for treating obstructed(sclerotic) vessel lumina in humans. In particular, this inventionrelates to a low profile guidewire drug delivery apparatus and methodsfor using a guidewire having an expansion member on which there isdisposed a therapeutic agent. In one aspect the present inventiondilates an obstruction within a vessel while simultaneously orsubsequently delivering a specified therapeutic agent or medicament doseto or adjacent to the dilatation site.

BACKGROUND OF THE INVENTION

It has become increasingly common to treat a variety of medicalconditions by introducing an implantable medical device partly orcompletely into the esophagus, trachea, colon, biliary tract, urinarytract, vascular system or other location within a human or veterinarypatient. For example, many treatments of the vascular system entail theintroduction of a device such as a stent, a catheter, a balloon, aguidewire, a cannula or the like.

Vascular disease, particularly cardiovascular disease, is commonlyaccepted as being one of the most serious health risks facing oursociety today. Diseased and obstructed coronary arteries can restrictthe flow of blood to the heart and cause tissue ischemia and necrosis.While the exact etiology of sclerotic cardiovascular disease is still inquestion, the treatment of narrowed coronary arteries is more defined.Surgical construction of coronary artery bypass grafts (CABG) is oftenthe method of choice when there are several diseased segments in one ormultiple arteries. Open heart surgery is, of course, very traumatic forpatients. In many cases, less traumatic, percutaneous methods areavailable for treating cardiovascular disease. For example, percutaneoustransluminal angioplasty (PTCA) balloons or excising devices(atherectomy) are used to remodel or debulk diseased vessel segments. Afurther treatment method involves percutaneous, intraluminalinstallation of expandable, tubular scaffolds or stents or prostheses insclerotic lesions.

Exposure, however, to a medical device which is implanted or insertedinto the body of a patient can cause the body tissue to exhibit adversephysiological reactions. For instance, the insertion or implantation ofcertain catheters or stents can lead to the formation of emboli or clotsin blood vessels. Similarly, the implantation of urinary catheters cancause infections, particularly in the urinary tract. Other adversereactions to implanted or temporary treatment whether introduced by anoperation or by a minimally invasive technique, include cellproliferation which can lead to hyperplasia, occlusion of blood vessels,platelet aggregation, rejection of artificial organs, calcification, andimpairment of device function.

For example, when a medical device is introduced into and manipulatedthrough the vascular system, the blood vessel walls can be disturbed orinjured. Clot formation or thrombosis, and/or cell proliferation oftenresults at the injured site, causing stenosis or “restenosis” (i.e.,closure) of the blood vessel. Additionally, if the medical device isleft within the patient for an extended period of time, thrombus mayform on the device itself with subsequent cell proliferation, againcausing restenosis. As a result, the patient is placed at risk of avariety of complications, including heart attack or other ischemicdisease, pulmonary embolism, and stroke. Thus, the use of such a medicaldevice can entail the risk of precisely the problems that its use wasintended to ameliorate.

Restenosis is the formation of new blockages at the site of theangioplasty or stent placement or the anastamosis of the bypass. Thereare two major mechanisms for restenosis. The first is by thrombosis, orblood clotting, at the site of treatment. The risk of thrombosis is thegreatest immediately after angioplasty, because the resultant tissuetrauma tends to trigger blood clotting. This form of restenosis isgreatly reduced by using anti-clotting drugs both during and after theprocedure.

The second form of restenosis is tissue growth at the site of treatment.This form of restenosis, a hyperproliferation of the vascular smoothmuscle cells that forms a layer in the wall of a blood vessel, tends tooccur during the first three to six months after the procedure, and isnot prevented by anti-clotting drugs. This form of restenosis can bethought of as resulting from exuberant or overly aggressive tissuehealing and regeneration after the trauma of angioplasty and/or stentplacement.

To reduce adverse effects caused by implanted medical devices, such asrestenosis, pharmaceuticals, such as anticoagulants andantiproliferation drugs, have been administered in or on stents orballoon catheters. These methods require release their activeingredients slowly. Indeed, prior art therapeutic methods generallyinclude slow controlled agent release.

Heretofore, various devices have been disclosed which may be used todeliver a therapeutic agent or medicament to a blood vessel whileundergoing angioplasty. Balloon angioplasty catheters have been used toplace and deliver a various therapeutic agents or medicaments withinhuman vessels. For example, in U.S. Pat. Nos. 5,112,305, 5,746,716,5,304,121, 5,674,192, 5,954,706, 5,569,197, 7,519,338, 7,488,314,7,473,242, 5,681,281, 5,873,852, 5,713,863, 6,997,947, 7,519,418,7,517,342, and 6,102,904 disclose and claim balloon/catheter systems fordelivering a drug into an arterial segment, the disclosures of each saidpatents being incorporated by reference herein in their entireties.

Alternatively a standard angioplasty balloon may be coated with apolymeric material which is then used to bond certain medicaments ortherapeutic agents. These agents are then delivered to the desiredtherapeutic site by inflation of the balloon and diffusion of themedicament or therapeutic agent into the vessel wall. Only limitedquantities of therapeutic agents can be delivered because of “wash-out”of the drug into the circulation during balloon placement and due to thelimited time the inflated balloon can be left in place due to ischemiacaused by the balloon.

In general, it is an object of the present invention to provide aguidewire-based dilatation device and method which is capable ofdilating an obstruction within a vascular segment while simultaneouslydelivering a therapeutic agent or medicament to the vessel segment.

Another object of the invention is to provide a guidewire-based devicethat can control the release or diffusion of a medicament or therapeuticagent to minimize potential systemic affects and maximize the diffusionor delivery of the medicament or therapeutic agent to the site oftreatment while permitting substantially uninterrupted vascular fluid,e.g., blood, flow.

Another object of the invention is to provide a device that is notsusceptible to structural damage (e.g., balloon rupture) and subsequentrelease of therapeutic agents or drug materials into the vasculature.

BRIEF SUMMARY OF THE INVENTION

Briefly, in one aspect, the present invention is guidewire-based methodsand apparatuses or devices of delivering drugs/agents to tissue in thebody, the drugs/agents having activity, such as anti-proliferativeactivity, in the vascular, particularly the endovasculature and moreparticularly, the cardiovascular system. This invention is useable aloneor in conjunction with one or more separate device(s) used to treatmedical infirmity or disease. The drugs used in this invention arecoated onto a distally disposed, therapy delivery portion or expansionmember of a guidewire and are released from the device segment orportion where they are deployed in a short time, preferably less than 10minutes, more preferably less than 5 minutes, and most preferably 60seconds or less upon member activation. Drug release or delivery isaccomplished, in one embodiment, by radial expansion of adrug-delivering or drug-supporting portion or surface, or expansionmember attached to and activated by expansion means of the guidewirewithin the vasculature, e.g., at the vascular blockage site. Methods ofreleasing the therapy also can include activating a trigger mechanism,or having the physiological conditions in the body e.g., temperature,pH, ionic balance, etc., trigger the drug release. Other methods andtechniques for guidewire-based expansion member activation includetorsionally-induced radial expansion of the member, hydraulic expansion,electro-mechanical expansion, use of shape memory materials which“remember” an expanded or collapsed state under defined conditions.

A method of the present invention comprises contacting the tissue orcirculation with a radially-expanding guidewire portion, member, orsegment which is coated with a therapeutic drug, agent or biologicalsubstance, wherein the agent is released into the circulation ordeposited onto the tissues surrounding the device in a short time afterthe contact (or immediately). The therapeutic agent is then quickly,effectively and efficiently absorbed or taken into the tissue, cells orinto circulation. The clear and unambiguous, critically importantadvantage of the guidewire-based approach taken here relative to otherendoluminal or endovascular drug delivery approaches is that use of aguidewire expansion member according to this invention provides aminimal diameter “low profile” therapeutic delivery. In practice of thisinvention precious radial intraluminal or intravascular space or “realestate” (as it is sometimes called) is not occupied with structures suchas balloon layers, catheter bodies, sheaths, and other device structuralfeatures. In short, the method/delivery of this invention permits accessto smaller, more tightly circuitous luminal structures, e.g., of smalleror more highly occluded vessels. It also permits drug delivery withoutischemic/schemic effects such as those caused by, for example, vesselblockage with a balloon.

Therapeutic drugs for coating the device include but are not limited tomedicines, proteins, adjuvants, lipids and other compounds whichameliorate the tissue or circulation surrounding the device.Additionally, the drug may be encapsulated in particles or controlledrelease carriers including liposomes, microparticles, and nanoparticles,which are coated upon the device, or bonded to it. Alternatively, thedrug may be an aggregate or flocculate of the drug or drug formulation.These drug aggregates are considered a type of particle, as describedherein. The therapeutic drug or drug formulation may have sustainedanti-proliferative activity and thus a prolonged effect. One example ofa group of drugs useful in the present invention to inhibitproliferative activity in the cardiovascular system, specifically smoothmuscle cell proliferation, are paclitaxel, sirolimus, everolimus, orABT-578 biological agents, such as cells and antibodies, could also beused to promote positive tissue growth or inhibit tissue growth orcellular proliferation contributing to or causing restenosis.

The terminology “coated,” “coated thereon,” “coated onto the guidewire”and common variations thereof is to be broadly interpreted to meandeposited, adhering, locally disposed as well as actually coated ontothe operant surface as in the working or expansion surface of aguidewire or a portion thereof. Those terms are intended to include thefull spectrum of possible adherent relationships between e.g., theexpansion member, and the drug or agent to be delivered. Those termsalso include what is primarily a physical interaction, e.g., a drugdelivery expansion member or means with a “roughened” surface.“Roughened” textured or porous surface drug retention and subsequentdelivery are known in the stent art.

The present invention comprises a substantially cylindrically shapedexpansion member deployed by and a part of the distal portion of aguidewire. It includes an expansion means engaged to the expansionmember for altering the distance between the proximal end and the distalend of the expansion member thereby transforming the expansion memberbetween a diametrically or radially contracted configuration and adiametrically or radially expanded configuration. A therapeutic agent ormedicament can be coated directly onto the expansion member oralternatively, the therapeutic agent or medicament can be incorporatedinto a polymer or other substrate and then coated on the expansionmember.

The present method also comprises the steps of advancing the guidewireincluding its expansion member e.g., an expandable mesh basket orballoon-like structure, to the obstruction in a vessel and applyingopposed forces on said expansion member (e.g., on its distal andproximal ends or portions) in an axial direction to move the expansionmember to an expanded configuration wherein the expansion member dilatesthe obstruction and the catheter/expansion member assembly actively (orpassively) delivers the therapeutic agent or medicament to theobstruction. Hydraulic, pneumatic, electrical or electro-mechanicalactualizations also are contemplated. Generally speaking this meansendovascular deposition of a drug or agent adjacent to or upon avascular blockage or site of medical interest.

The present method also comprises the steps of advancing its expansionmember of the guidewire to e.g., an obstruction in a vessel and applyingopposing or opposed forces on said expansion member in an axial orrotational direction to move the expansion member to an expandedconfiguration wherein the expansion member dilates the obstruction andthe guidewire/expansion member assembly actively (or passively) deliversthe therapeutic agent or medicament to the obstruction. Opposing forcesas used here includes static force, or simply resistance to applicationof kinetic (moving) force, static force includes, for example, one endof the expansion member being anchored or attached to a guidewirestructure which resists axial or rotational movement causing theexpansion member to expand.

In yet a further embodiment, the present invention relates to aguidewire having a guidewire expanding member which, in turn hasparticles dispersed or coated on its surface, each particleencapsulating a therapeutic drug or agent(s), or a combination oftherapeutic drugs, having anti-proliferative activity in e.g., thecardiovascular system. The particles may preferably be liposomes,microparticles or nanoparticles. The guidewire expanding member orstructure is contacted with surrounding tissue or deployed intocirculation such that the therapy is released from the particle and intothe surrounding tissue or circulation depending upon the medical problemand/or its treatment.

The method of the invention allows the release of drugs or agent anddrug or agent formulations from a low profile guidewire structure i.e.,a device, that is not permanently implanted in the body. A “low profile”guidewire as that term is used herein is one in which there is no morethan about a 10%, preferably less than about 5%, and most preferableless than about 2% variation in diameter a profile from one end of thedevice to the other. In other words, essentially the only variation indiameter of this device is the thickness of the drug coating thereonwhen the guidewire is in the unexpanded, vessel navigation state.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows in section a drug delivery guidewire of this invention innavigation to a site of medical interest state.

FIG. 2 shows one of the guidewires of FIG. 1 in a drug oragent-deployment or agent delivery state.

FIG. 3 is a second embodiment of an expansion member of this invention.

FIG. 4 is in part a side view, in part a cross-sectional view throughthe outer and inner coils and in part a cross-sectional view through theouter coil and a side view of the inner coil of a cable (sometimescalled a torque cable) useable in this invention (e.g., as the expansionmeans or movement mechanism) and a cross-sectional view through a partof a connector or coupling, a number of axial intermediate parts beingbroken away (U.S. Pat. No. 5,678,296 to Fleischhacker et al describesthis torque cable, the entire disclosure of which is incorporated byreference herein).

FIG. 5 is a side view of a part of an axial length of a torquecable/expansion means in this invention indicating its flexibility.

FIG. 6 is a side view of manually operated medical apparatus thatincludes a control member, a medical subassembly, and the torque cablecoupling or connecting with nearly 1:1 torque transmission the controlmember and medical subassembly being diagrammatically illustrated.

FIGS. 7 and 8 show in section an embodiment of this invention in which amonofilament expansion member is displayed on the distal end, portion orsegment of a guidewire.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of delivering drug(s),agent(s), cells or biological substances (the term “agent” includesdrugs, biological substances, and biologics as those terms are used intheir arts) in a target-specific manner, through the use of a drug ortherapy-coated guidewire segment, portion or member, which includes drugdelivery means and guidewire structure. The claimed method provides atherapy that targets the traumatized area by proximity alone or incombination with a systemic effect i.e. delivery from an exteriorsurface of a guidewire. A drug of the present invention provides, forexample, anti-proliferative therapeutic activity to the cardiovascularsystem. A drug of this invention generally is effective locally, i.e.,at the site of vessel contact, but may have more general systemiceffects. A drug deployed by means of the present invention does notrequire a delayed or long term release and can be used, e.g., toactivate anti-proliferative activity immediately upon contact with thecells of the target tissue or circulation. The drug may have sustainedanti-proliferative activity and thus, a prolonged effect. The drug ispreferably released in less than about or equal to one minute from thetime of its initial contact with the tissue or circulation althoughlonger drug release time will often be used depending upon the drug, thespecific therapy and related indications and side effects. FIGS. 4 and 5shown in section an embodiment of this invention in which a monofilamentexpansion member is used.

The drugs or agents coated upon the guidewire surface, e.g., aradially-expanding surface, and thus useful in the present invention aredelivered to the target tissue in a short time after the device'sinitial contact with the targeted tissue or surrounding circulation,i.e., there is a relatively quick release of the drug from the guidewireto the tissue. The drugs which can be used in the present inventionprovide, in one approach, anti-proliferative activity in thecardiovascular system. Other agents may promote tissue growth toexpedite vessel healing, e.g. anti-h-CO54 antibody.

In one embodiment, the activity of the drug may be sustained and thedrug exhibits a prolonged anti-proliferative effect. Therefore, the drugdoes not require a delayed or prolonged release and as such, the releasecan be immediate. Accordingly, the drug may be attached to a working ordelivery surface of the device that is not a permanent implant butrather briefly contacts the tissue or circulation. Additionally, due toits sustained effect, the drug may also be encapsulated in a particlewhich may enhance its uptake by the target tissue or cells.

The drugs may be directly applied to the guidewire expansion member in acomposite, wherein the drugs are mixed with other reagents, or may beencapsulated within drug release particles such as liposomes,microparticles, nanoparticles, or aggregates of the drug. The particlesmay include inert polymeric particles, such as, for example,microparticles or nanoparticles. Alternatively, the particles maycomprise biologically derived reagents, such as, for example, lipids,sugars, carbohydrates, proteins and the like. Specifically, suchparticles are release carriers which provide an effective release of thetherapeutic agent to the target tissue or cells. The therapeutic agentformulation may be specifically taken up by cells of the whiteblood-cell lineage, such as macrophages or monocytes. By this means, thedrugs are delivered in a target-specific manner, without the need toprovide a full dosage of drugs to the entire body through conventionaldrug delivery routes as discussed above. Indeed, providing thetherapeutic agent in a localized manner or to specific cells can avoidthe undesired side effects of such large doses. The drug releasecarriers are preferably biodegradable, so that when they are broughtinto contact with the target tissue or circulation or when taken intospecific cells, the drug or therapeutic agent is quickly released fromthe carrier, and then the biodegradable carrier is itself, in due time,removed by natural body processes.

In one embodiment of the present invention the particles or releasecarriers include, but are not limited to, semi-synthetic polyacrylstarch microparticles, other biodegradable microparticles containing thetherapeutic agent, ethyl cellulose, poly-L-lactic acid, heptakis(2,6-di-O-ethyl)-beta-cyclodextrin, polyalkylcyanoacrylate nanocapsules, polymethylacrylate, monocarboxycellulose, alginic acid,hyaluronic acid, lipid bilayer beads, polyvinylpyrollidone, polyvinylalcohol, albumin, lipid carriers of continuous phase (non-microparticletype), nanoparticles, and known agents by those skilled in the art forthe release of therapeutic agents. Nanoparticles are preferablyspherical or non-spherical polymeric particles that are 30-500 nm indiameter.

In a further embodiment of the present invention, the therapeutic agentor drug may be encapsulated within, or form itself, a liposome, colloid,aggregate, particle, flocculate or other such structure known in the artfor encapsulation of drugs. The encapsulation material itself may have aknown and predetermined rate of biodegradation or bioerosion, such thatthe rate of release and amount released is a function of the rate ofbiodegradation or bioerosion of the encapsulation material. Preferably,the encapsulation material should provide a relatively quick releaserate.

In yet a further embodiment of the present invention, the particles, orrelease carriers, may be supported within the matrix of amacrostructure. Particles or controlled release carriers, as previouslydiscussed, include, but are not limited to microparticles,nanoparticles, colloids, aggregates, liposomes, particles, orflocculates. Materials used to provide the macrostructure include, butare not limited to, fibrin gels, hydrogels, or glucose. Non-limitingexamples of particles supported within a macrostructure include a fibringel with colloid suspended within it; a hydrogel with liposomessuspended within it; a polymeric macrostructure with macroaggregatedalbumin suspended within it; glucose with liposomes suspended within it;or any of the foregoing further including liposomes, flocculantsmicroparticles, nanoparticles, or other particles containing or havingdispersed therein a drug or therapeutic agent. In the use of thisinvention it need not be that the macrostructures nor the particles beentirely bioabsorbed. For example if fibrin or collagen is used toprovide the macrostructure, such materials are biodegradable yet canpersist in the extracellular matrix for substantial lengths of time.

In one embodiment of the invention, the drug or therapeutic agent isencapsulated within liposomes. Liposomes may be submicroscopic, i.e.,preferably no greater than 100 nm in size, capsules consisting of adouble membrane containing various lipids. One such lipid is aphospholipid, a natural material commonly isolated from soy beans.Liposomes are nontoxic and generally recognized as safe by the FDA.Liposomes can be characterized as a hollow flexible sphere containing anaqueous internal compartment surrounded by an external aqueouscompartment. Any material trapped inside the liposome is protected fromthe external aqueous environment. The lipid bilayer acts as a barrierand limits exchange of materials inside, with materials outside themembrane. Furthermore, the lipid bilayers are hydrophobic and can“entrap” and retain similar types of substances. The rate of release ofan encapsulated therapeutic agent or drug from a liposome can be, forexample, controlled by varying the fatty acid composition of thephospholipid acyl groups, or by providing elements which are embedded inthe lipid bilayers, which specifically allow a controlled and rapidrelease of the encapsulated drug from the liposomes. In practice,chemical modification of the phospholipid acyl groups is accomplished byeither chemically modifying the naturally derived materials, or byselecting the appropriate synthetic phospholipid. The embedded elementsin the liposome may be biologically- or bioengineering-derived proteins,polypeptides or other macromolecules to selectively provide pores in theliposome wall.

Liposomes are highly advanced assemblages consisting of concentricclosed membranes formed by water-insoluble polar lipids. The lipidscomprising the membrane may be selected from the group consisting ofnatural or synthetic phospholipids, mono-, di-, or triacylglycerols,cardiolipin, phosphatidylglycerol, phosphatidic acid, or analoguesthereof. Preferably, the liposome formulations are prepared from amixture of various lipids.

The natural phospholipids are typically those from animal and plantsources, such as phosphatidylcholine, phosphatidylethanolamine,sphingomyelin, phosphatidylserine, or phosphatidylinositol. Syntheticphospholipids typically are those having identical fatty acid groups,including, but not limited to, dimyristoylphosphatidylcholine,dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine,distearoylphosphatidylcholine and the corresponding syntheticphosphatidylethanolamines and phosphatidylglycerols.

Other additives such as cholesterol, glycolipids, fatty acids,sphingolipids, prostaglandins, gangliosides, neobee, niosomes, or anyother natural or synthetic amphophiles can also be used in liposomeformulations, as is conventionally known for the preparation ofliposomes.

Stability, rigidity, and permeability of the liposomes are altered bychanges in the lipid composition. Membrane fluidity is generallycontrolled by the composition of the fatty acyl chains of the lipidmolecules. The fatty acyl chains can exist in an ordered, rigid state orin a relatively disordered fluid state. Factors affecting rigidityinclude chain length and degree of saturation of the fatty acyl chainsand temperature. Larger chains interact more strongly with each other sofluidity is greater with shorter chains. Saturated chains are moreflexible than unsaturated chains. Transition of the membrane from therigid to the fluid state occurs as the temperature is raised above the“melting temperature”. The melting temperature is a function of thelength and degree of unsaturation of the fatty acyl chain. In oneembodiment, the liposomes, drug aggregates, microparticles, ornanoparticles are created in a pre-selected size that is preferablytaken up by macrophages and monocytes. Thus, the liposomes act withinthe macrophages to incapacitate them or to inhibit their activity. In apreferred embodiment of the present invention, the liposomes are greaterthan 100 nm.

In addition to temperature and lipid composition, inclusion of a sterol,such as cholesterol, or a charged amphiphile can alter the stability,rigidity and permeability of the liposome by altering the charge on thesurface of the liposome and increasing the distance between the lipidbilayers. Proteins and carbohydrates may be incorporated into theliposomes to further modify their properties. (See U.S. Pat. No.4,921,757 entitled “System for Delayed and Pulsed Release ofBiologically Active Substances,” issued May 11, 1990).

The therapeutic agent either directly coated upon or encapsulated andsuspended upon a guidewire shall be quickly released into thesurrounding tissue or circulation of the cardiovascular system once theguidewire has been implanted or reaches the target area.

Optionally, it may be desirable to position a porous layer over thelayer of therapeutic drug coated upon the guidewire or guidewireportion, in order to protect the therapeutic drug from releasingprematurely from the guidewire, that is, prior to reaching its targettissue or circulation. Additionally, the porous layer may also bepositioned over the layer of microparticles or nanoparticlesencapsulating the therapeutic drug. If utilized, the porous layer ispreferably biodegradable and slowly consumed during the insertion ordeployment of the guidewire, but can also be an inert stable layer. Thethickness and type of material used to construct the porous layer ischosen based on the type of device, the insertion or deployment methodused, and the length of time the device is in contact with body fluidsprior to reaching its target tissue or circulation. Thus, variousdevices and applications require porous layers which degrade atdifferent rates. However, most of the porous layer is preferablydissolved by the time the guidewire reaches its target tissue orcirculation in order for the therapeutic agent to be quickly andeffectively released.

Alternatively, instead of a porous layer deposited over an existinglayer of microparticles or nanoparticles, the material of theseparticles may be selected such that the biodegradation or bioerosion ofthe encapsulation material occurs at a rate which does not allow thetherapeutic agent to be released prematurely.

The release profile of the drug from the microparticles or nanoparticlesis determined by many factors including the drug solubility and thethickness and porosity of the microcapsules. The microcapsules of theinvention may either be rupturable to release their contents or may bedegradable such that they will open when left against the lumen walls.Thus, the particles or capsules may release their contents throughdiffusion or by rupturing due to the application of external forces. Theparticles or capsules may also be consumed by the phagocytic,chemotactic, and cytotoxic activities of surrounding cells. For example,macrophages are important killer T-cells and by means ofantibody-dependent cell-mediated cytotoxicity (ADCC) they are able tokill or damage extracellular targets. Additionally, the drugs may bereleased by activating a trigger mechanism, or having it activatedpassively by the physiological conditions.

In one embodiment of the invention, the drug-coated guidewire expansionmember can be configured as at least one of, or any portion of, acatheter, an angioplasty device, a stent, a vascular or other graft, acardiac pacemaker lead or lead tip, a cardiac defibrillator lead or leadtip, a heart valve, a suture, a needle, a guidewire, a cannula, apacemaker, a coronary artery bypass graft (CABG), an abdominal aorticaneurysm device (Triple A device) or an orthopedic device, appliance,implant or replacement. In a further embodiment, the guidewire can alsobe configured as a combination of portions of any of these devices. Thedrug may be coated on the entire surface of the medial device or aportion thereof. For example, the entire structure may be coated with atype of therapeutic agent, or only a specific portion, which willcontact a target area, may be coated.

Reference now is made to the FIGS. 1-2 in which there is shown aguidewire 10. Guidewire 10 has a central core wire 12 which ends in anatraumatic, bulbous or bullet-shaped tip 14. Proximal to tip 14 is (inthis embodiment) a radiopaque coil 16. Coil 16 is connected to centralcore wire 12 and tip 14 e.g., by soldering adhesives or welding.Proximal to coil 16 is an expansion member 18 which in this example is aseries of interwound, (e.g. woven), radially expandable drug-coatedstruts 20. Struts 20 tend to operate as a unit or member so thatapplication of force to the more proximal end 24 of struts at 22 causesthe struts to expand radially outward away from the central axis of corewire 12 generally corresponding to a line down the middle of core wire12, e.g., dashed line 13 in FIG. 1 and toward, e.g., the inside of avessel. Force is applied to the more proximal end 24 of woven struts 20by expansion means 26 which in this embodiment is a substantiallylongitudinally rigid or “stiff” tubular member 28 which is both“pushable” (or steerable) and “torquable” as those terms are used in theart. (See, e.g., FIGS. 7 and 8). Various other mechanisms to causeexpansion member 18 to expand radially e.g., proximal application ofradial torque to a counter-wound, 1:1 torque-transmissive coil, willreadily be appreciated by one skilled in this art in light of thisdisclosure. Tubular member 28 has an inside diameter which is justsufficiently larger than the outside diameter of core wire 12 so as toslideably engorge therewith. It will be appreciated that tubular member28 will have substantially the same rigidity and steerability as corewire 12 so as to cooperate therewith while the guidewire 10 is beingdirected into the vasculature. Application of distally-directed force totubular member 28 causes expansion member 18 to expand radially andhence to deploy drug or agent (not shown) coated thereon into and ontothe endovasculature, its distal end 25 being held in place by theproximal end 27 of radiopaque coil 16.

FIG. 1 is generally the configuration of guidewire 10 of this embodimentof the invention during navigation of the guidewire to and through thevessel site to be treated.

FIG. 2 shows the configuration of guidewire 10 with expansion member 18in its expanded or delivery state 18. Proximal retraction of tubularmember 28 will cause expansion member 18, i.e., the strut structure,radially to contract so as to return generally to its navigationconfiguration and for further proximal withdrawal of guidewire 10.During the expanded state, expansion means or member 26 delivers drug oragent to the site of medical interest, the drug or agent being chosen toaddress the medical issue e.g., blockage, restenosis, inflammation,which makes the deployments site medically of interest. Expansion member26 may have an inherent tendency or bias to return to its non-expanded,navigation state. Whether an expansion member does or does not have atendency to return to a smaller diameter will determine howaffirmatively tubular member 28 is attached to the proximal end ofexpansion member 26 as well as to the structure on its distal end.

FIG. 3 is a second embodiment of a guidewire expansion member 30 of thisinvention. Expansion member 30 is a mesh or woven cylindrical structurecomprising individual woven or overlapping struts, strands, helices orwires 32. Member 30 has a distal end 34 and a proximal end 36(physician's frame of reference). Proximal end 36 of mesh expansionmember 30 has a shoulder or ridge 38 as does distal end 34 (at 40). Inthis variation expansion member 30 is attached to expansion means 42which, as above, is a hollow flexible tubular member. Expansion member30 is basket-like, bulbous or prolate comprising interwoven strandstending to act like an integrated unit or entity. Expansion member 30slideably engages guidewire core wire 44. Distal end 34 of meshstructure 32 is affixed to guidewire 42. Application of distal force totubular member 42 causes mesh structure 32 to expand radially anddeliver endovascularly any drug or agent (not shown) disposed thereon.Similarly, the expansion member could be a distal coil, segment, orportion (not shown) that expands and contracts radially as rotationaland/or translational force is applied to its proximal end or segment.

Referring to FIG. 4, a torque cable useable in this invention, generallydesignated 410, includes an inner coil M made up of a single layer ofmultifilar helically wound coil of wires, preferably four wires 411,412, 413, and 414 that has each convolution (helix) of one wire incontact with the adjacent convolution of two other wires. While amultifilar torque cable is preferred, monofilar coils (i.e., a singlehelically-wound wire) are also contemplated. The inner coil is wound tobe, in a relaxed non-assembled condition, a coil having an innerperipheral diameter W and a coil outer peripheral diameter Z. The cable410 also includes an outer coil N made up of a single layer ofmultifilar helically wound coil of wire, preferably four wires 416, 417,418, and 419 that are wound in the opposite direction from the windingof the inner coil, and likewise has adjacent wire convolutions incontact with one another. The outer coil is wound to in a relaxednon-assembled condition have a coil inner peripheral diameter X and acoil outer peripheral diameter Y. For example the inner coil outerperipheral diameter in a non-(W) assembled condition may be about 0.002″greater than the outer coil inner peripheral diameter in a non-assembledcondition (X). The torque cable discussed herein could also be used withor coupled to tubular member 28 to comprise an expansion means as thatterm is used herein. The torque cable could also be coupled to a distalcoil segment as is discussed in the previous paragraph.

In order to assemble the torque cable, the outer coil is partiallyunwound by applying an unwinding force to increase the coil innerperipheral diameter. Then the inner coil is inserted into the partiallyunwound outer coil and thence the unwinding force that was applied tothe outer coil is released. The axial central part of the outer coilstarts to shrink first to form an interference fit with the inner coiland continues to shrink its outer coil diameter toward the outer coilopposite ends whereby there is obtained an interference fit throughoutthe entire axial length of the cable. All of the helices of each of thecoils in the assembled condition of the coils are of substantially thesame inner and outer diameters throughout the axial lengths of the coilswhile the inner and outer coils are of substantially the same axiallengths. That is the helices of each coil are of substantially the sameradial spacing from the respective coil central axis C-C.

By assembling through partially unwinding the outer coil and allowing itto contract after the inner coil has been inserted, the cable 410 may bymade of an outer diameter of about 1/16″ or less and bent through, forexample, a circular configuration portion 10 a of a radius of curvatureR of, for example about 1″ or/and “S” curved portions 10 b, 10 c radiiof curvature such as illustrated in FIG. 5.

Referring to FIG. 6, the medical apparatus K includes a cable 610 thathas its proximal end portion fixedly attached to an optional manuallyoperated control member H while the distal end portion mounts andcouples to a medical subassembly P, the control member and medicalsubassembly being diagrammatically illustrated. Medical subassembly P,in this embodiment of the invention is e.g., a guidewire expansionmember portion, segment, or working surface according to this invention.(Guidewire core wire 612 is shown and designated by broken lines). Forexample, expansion member P would comprise a woven structure, basket,bulbous member, which when torque was applied to central member H, wouldbe transmitted on a substantially 1:1 basis by counter-wound torquecable 610 to the proximal end 614 of subassembly P and cause thesubassembly P (the distal end of subassembly P presumably being anchorede.g., at the guidewire tip (not shown)) to expand radially. Agent coatedon subassembly/expansion member P would then be endovascularly deliveredeither locally or systemically.

FIGS. 7 and 8 illustrate in section a further embodiment of the presentinvention. FIG. 7 depicts the device in its vascular navigation stagewhile FIG. 8 shows the device in its drug delivery stage.

In FIG. 7 the guidewire 40 includes an expansion member 42 whichcomprises a single helically-wound filament or wire 44. Multi-filarexpansion members also could be used.

Guidewire 40 comprises a core wire 46 and a radiopaque coil 48. Corewire 46 and radiopaque coil 48 are coupled to each other e.g., bysolder, spot weld or adhesive, at distally-extreme, atraumatic tip 50.

Expansion member 42 has a distal end or portion 52 and a proximal end orportion 54. As is shown expansion member distal end 52 abuts radiopaquecoil 48 at the coil's proximal end 56 and is thereto affixed to corewire 46. Expansion means or torsion mechanism 58 is, in this embodiment,a hypotube segment having an inside diameter which is about the same as,but slightly larger, than the outside diameter of guidewire core wire 46at its proximal length. Hypotube 58 is substantially longitudinally ortorsionally rigid such that proximally applied, torque ordistally-directed force (e.g., arrow 60) is efficiently transmitted toexpansion member 42 proximal end 54.

FIG. 8 shows the guidewire of FIG. 7 as it appears when member 42′ is inthe expanded state, e.g., when delivering a drug or agentendovascularly, alone or in conjunction with a luminal opening andexpansion of a vessel. Drug or agent (not shown) is or would be coatedat least on the outermost segment 62 (only shown in FIG. 8) of filamentor wire 44. (Filaments 44 could also be completely coated with drug,agent, or biologic). Expansion member 42′, in this embodiment, is shownto be substantially conical with a slightly distally decreasing, outwarddiameter. As in the earlier embodiments, expansion member 42, 42′ isdisposed along and is collinear with core wire and tapers in parallelwith taper 64. Outside segments 62 are shown to be substantially planar.Such a configuration could be obtained e.g., by differential temperingor treating of individual expansion member helices 44. In this manneroverall guidewire outside diameter is kept to a minimum even during drugdelivery and/or concurrent or separate vessel angioplasty.

In a preferred embodiment, a drug-coated or drug bound guidewire,working surface or guidewire portion (usually but not necessarily anexpansion member) is utilized to release the therapeutic agents havinganti-proliferative activity into the body tissue or circulation.

The therapeutic agent, preferably encapsulated in a particle or acontrolled release carrier, or aggregated to a desirable/pre-selectedsize, for efficient uptake by a macrophage, is applied to the surface ofthe guidewire by coating methods known in the art, including, but notlimited to spraying, dipping, rolling, brushing, solvent bonding,adhesives or welding or by binding the microparticle or aggregates tothe surface of the guidewire by any chemical method known in the art.Furthermore, if the guidewire has folds, corrugations, cusps, pores,apertures, or the like, the therapeutic agent or particle encapsulatingthe therapeutic agent may be embedded, i.e., mechanically trapped,within the guidewire without the use of adhesives. In addition to thedrug coated on the guidewire, an additional dosage of the therapeuticdrug, which inhibits proliferation in the cardiovascular system, may beapplied by conventional delivery methods discussed above, (e.g., orally,intravenously) or may be injected through the guidewire. For example,the therapeutic drug may be injected through the guiding catheter viathe same method and procedure used to inject the contrast dye commonlyused during a PTA. The particles are preferably selected from the groupconsisting of lipids, microparticles, nanoparticles, or the drug itselfin aggregates, flocculates or the like.

The therapeutic drugs useful in the present invention preferably inhibitthe proliferation of vascular smooth muscle cells. In one embodiment,the therapeutic drugs directly alter smooth muscle cell activity byaltering cellular metabolism, inhibiting protein synthesis, orinhibiting microtubule and microfilament formation, thus affectingmorphology. The therapeutic drug may also include inhibitors ofextracellular matrix synthesis or secretion. Thus, in one embodiment,the methods and dosage forms of the present invention are useful forinhibiting vascular smooth muscle cells by employing a therapeutic agentthat inhibits the activity of the cell, i.e. inhibits proliferation,contraction, migration or the like, but does not kill the cell. However,in a further embodiment, the methods and dosage forms of the presentinvention are useful for inhibiting target cell proliferation byemploying a therapeutic agent that is cytotoxic to the cell.

The therapeutic agent, may directly or indirectly inhibit the activityof the smooth muscle cells, thus inhibiting or suppressing proliferationof the smooth muscle cells. For example, in one embodiment, thetherapeutic agent may directly inhibit the cellular activity of thesmooth muscle by inhibiting proliferation, migration, etc. of the smoothmuscle cells. In a further embodiment, the therapeutic agent may inhibitthe cellular activity of surrounding cells, whose activity initiates,assists or maintains proliferation of smooth muscle cells. Thus, smoothmuscle cell proliferation is indirectly inhibited or suppressed by theinhibition or suppression of the metabolic activities of the surroundingcells, whose activities maintain smooth muscle cell proliferation.

In a preferred embodiment, the therapeutic drug encapsulated and coatedon the guidewire is used for reducing, delaying or eliminatingrestenosis following angioplasty. Reducing restenosis includesdecreasing the thickening of the inner blood vessel lining that resultfrom stimulation of smooth muscle cell proliferation followingangioplasty. Delaying restenosis includes delaying the time until onsetof visible hyperplasia following angioplasty, and eliminating restenosisfollowing angioplasty includes completely reducing and/or completelydelaying hyperplasia to an extent which makes it no longer necessary tointervene. Methods of intervening include re-establishing a suitableblood flow through the vessel by methods such as, for example, repeatangioplasty and/or stent placement, or CABG.

One example of a group of drugs useful in the present invention toinhibit proliferative activity in the cardiovascular system,specifically smooth muscle cell proliferation, are bisphosphonates (BP).Bisphosphonates, formerly called diphosphonates, are compoundscharacterized by two C—P bonds. If the two bonds are located on the samecarbon atom (P—C—P) they are termed geminal bisphosphonates.Bisphosphonates indirectly inhibit smooth muscle cell proliferation bymetabolically altering surrounding cells, namely macrophages and/ormonocytes. Bisphosphonates when encapsulated in liposomes ornanoparticles or aggregated in aggregates of a specific size, aretaken-up, by way of phagocytosis, very efficiently by the macrophagesand monocytes. Once inside the macrophages, the liposomes are destroyedand release the encapsulated bisphosphonates, which inhibit the activityof the macrophages. Since macrophages, in their normal state, arerecruited to the areas traumatized by angioplasty or other intrusiveintervention and initiate the proliferation of smooth-muscle cells(SMC), inhibiting the macrophages' activity will inhibit theproliferation of SMC. Once released and taken-up by the macrophages, thebisphosphonates will have a sustained anti-proliferative activity forthe lifetime of the macrophages. Thus, prolonged release of thebisphosphonates is not required in order to sustain inhibition.Representative examples of bisphosphonates suitable for use in thepresent invention are alendronate, clodronate, and pamidronate.

In a preferred embodiment of the present invention, the therapeutic drugis encapsulated in relatively large liposomes that are preferably takenup by cells such as monocytes and macrophages. The structure andcomposition of the liposomes are discussed supra. Additionally, theliposomes may be greater than 100 nanometers in size and contain, forexample, a bisphosphonate drug.

In one embodiment, the drug, such as, for example, a bisphosphonate maybe encapsulated in a liposome and coated upon a suitable guidewire.Coating methods and suitable guidewires are discussed supra. Forexample, the liposomal bisphosphonates may be coated on a ballooncatheter and suspended in a macrostructure such as glucose or gelatin,or chemically bound to the surface. Thereafter, the balloon catheter iseffectively maneuvered through the cardiovascular system and to anocclusive site. Once in the proper position, the balloon is inflatedinto contact with the lumen to be treated. The liposomes, whichencapsulate the bisphosphonate therapeutic drugs, are then released fromthe guidewire and are present in the tissue and in the circulation,ready for uptake by macrophages, locally and systemically.

Upon the release of the liposomes into the lumen of the affected areaand immediate uptake by the macrophages, restenosis is inhibited. Forexample, bisphosphonates may prevent monocytes from developing intomacrophages by altering their cellular metabolism. Furthermore, the BPmay also inhibit cellular activity of macrophages thereby altering theirbiological function as the central effector and regulatory cell of theinflammatory response. Therefore, while macrophages are recruited to thetraumatized area, these cells can not initiate the inflammatory processthat turns into restenosis. The release of the Liposomal BP (LBP) can becarried out systemically and/or locally, and is taken-up by macrophagessystemically and locally.

The therapeutic agent may also promote the growth of smooth muscle cells(c.s. anti-h-CO54 antibody or stem cells), which promotes tissue growthand healing to prevent an inflammatory and/or thrombogenic-basedrestenosis.

In a further embodiment, the guidewire may also carry therapeuticagents, such as, for example, anti-spasmodic, anti-thrombogenic, andanti-platelet agents, antibiotics, steroids, and the like, inconjunction with the anti-proliferative agent, to provide localadministration of additional medication.

It is to be understood that the embodiments and variations shown anddescribed herein are merely illustrative of the principles of thepresent invention. Therefore, various adaptations and modifications maybe implemented by those skilled in the art without departing from thespirit and scope of the present invention.

1. A method of delivering an agent to vascular tissue using a guidewire,the method comprising: contacting the tissue with an agent-deliveringsurface of a guidewire the surface having an agent disposed thereon; andpermitting the agent to be delivered to the tissue by maintainingcontact between the agent-delivery surface and the tissue a sufficienttime for agent delivery to occur.
 2. A method according to claim 1wherein the guidewire surface comprises a portion of a guidewireexpansion member.
 3. A method according to claim 1 wherein the agent isa drug.
 4. A method according to claim 1 wherein the agent is abiological substance.
 5. A method according to claim 1 wherein contactbetween the agent-delivery surface and the tissue is maintained for lessthan or equal to one minute.
 6. A method according to claim 1 whereinthe agent-delivering surface is the outside surface of a guidewireexpansion member.
 7. A method according to claim 6 wherein the expansionmember comprises a radially-expandable, interwound cooperating series ofstruts.
 8. An agent-delivery guidewire, the guidewire having distal andproximal portions, and a core wire which defines a guidewire axis, thedistal portion including an expansion member, the expansion memberhaving an agent coated on an outside surface thereof and being coupledto the core wire.
 9. An agent-delivery guidewire according to claim 8which further includes a proximally located expansion means, said meanscoupled to said expansion member so that when activated the expansionmeans causes the expansion member to expand radially outward from theaxis of the guidewire.
 10. An agent-delivery guidewire according toclaim 9 wherein the expansion means in a hypotube which is slideablydisposed over the core wire and coupled to the expansion member on itsproximal end.
 11. A guidewire of claim 10 wherein the expansion membercomprises radially expandable interwound struts.
 12. An agent-deliveryguidewire according to claim 10 wherein the expansion means is acounter-wound coil disposed over the core wire proximal to the expansionmember, the counter-wound coil providing approximately 1:1 torquetransmission to the proximal end of the expansion member permittingradial expansion of the expansion member by proximal application ofradial torque.
 13. A guidewire method of endovascular agent deliverycomprising the steps of: advancing a guidewire through a vessel to asite of treatment to which the agent is to be delivered, the guidewireincluding an expansion member having agent coated thereon; applyingopposing forces to the expansion member to cause it to expand radiallyoutwardly, from the axis of the guidewire to the site of treatment;permitting the expansion member endovascularly to deliver the agent tothe site of treatment by maintaining the expansion member at the site oftreatment for a time sufficient to deliver the agent; removing theopposing forces applied to the expansion member to permit the expansionmember to return to its radial dimension during the advancing stepwithdrawing the guidewire from the vessel.
 14. A method according toclaim 13 wherein the expansion member is maintained at the site oftreatment for less than 5 minutes.
 15. A method according to claim 13wherein the expansion member is maintained at the site of treatment forless than 1 minute.
 16. A method according to claim 13 wherein vesseldilation occurs simultaneously with agent delivery by the radialexpansion of the expansion member.
 17. Guidewire for delivering amedicament to an obstruction within guidewire apparatus, a vascularsegment or a body passageway which comprises: a guidewire having adistal end and a proximal end; a substantially cylindrical shapedexpansion member located on the distal end of the guidewire, theexpansion member including first and second ends and comprising aplurality of flexible elongate elements, the flexible elongate elementscomprising: a first set of elements having a first common direction ofrotation crossing a second set of elements having a second commondirection of rotation opposite to that of the first direction ofrotation to form a mesh, the mesh having on its outward most surface anagent coated thereon. a movement mechanism which causes the expansionmember to change configuration between a first configuration wherein theexpansion member is characterized by a first diameter and a secondconfiguration wherein the expansion member is characterized by a seconddiameter, the second diameter being greater than the first diameter.